Linear polyamines, like spermine (SPM, 1) and spermidine (SPD, 2), and their compounds with other natural products, collectively coined as polyamine conjugates, are widely distributed in living organisms and exhibit interesting biological properties.

In order to determine structure-biological activity relationships and possibly identify lead compounds for the development of polyamine-based pharmaceuticals, a variety of linear, branched, conformationally restricted and cyclic polyamine analogues and conjugates have been synthesized (Blagbrough et al., PHARM. SCI., 3, 223 (1997); Schulz et al., ANGEW. CHEM. INT. END. ENGL., 36, 314 (1997); Papaioannou et al., EUR. J. ORG. CHEM., 1841 (2000) and Kong Thoo Lin et al., SYNTHESIS, 1189 (2000)). Due to their polycationic nature, polyamines interact strongly with nucleic acids and play an important role in their biosynthesis and metabolism. They stabilize DNA conformation and can induce conformation changes through the formation of intra- or intermolecular bridges. Polyamines cause specific modifications of specialized RNA molecules, stabilize ribonucleases and stimulate the action of ribonucleases and ribozymes. They exert pleiotropic effects on protein synthesis, are essential for normal growth and involved in the differentiation processes of mammalian cells. The concentrations of polyamines and the enzymes responsible for their biosynthesis are notably higher in rapidly proliferating mammalian cells; generally, these concentrations increase in all cells upon induction of differentiation. Polyamines are directly responsible for the increased rate of the macromolecular synthesis occurring during tumour development and growth. Inhibition of the biosynthetic enzymes producing polyamines and of the polyamine uptake system responsible for feeding the cell with exogenous polyamines have emerged as very attractive targets for cancer chemotherapy. Recently, selectively N-alkylated polyamines which partially mimic natural polyamine behaviour, inhibit cell growth and are metabolically stable have been developed as novel anticancer agents (for leading references see the review by Papaioannou et al., EUR. J. ORG. CHEM., 1841 (2000)).
The retinoids constitute a large family of organic compounds structurally related to the naturally occurring Vitamin A (retinol, 3) and analogues, such as retinal (4) and all-trans-retinoic acid (5) and a variety of other synthetic analogues, such as acitretin (6), 13-cis-retinoic acid (7) and 9-cis-retinoic acid (8). The polyene chain-shortened all-trans-retinoic acid analogues 9 and 10 may be also considered as members of this family.

Retinoids can cause specific biological responses upon binding to and activating special receptors or groups of receptors. Natural and synthetic retinoids play an important role in vision, cell growth, reproduction, proliferation and differentiation of various epithelial or non-epithelial tissues. Although they are already widely used in systemic and topical treatment of various disorders, retinoids reveal a considerable number of side-effects even when used in therapeutic doses. Thus, numerous new retinoid analogues have been synthesized in an attempt to improve the therapeutic index, biological profile and selectivity of these compounds for clinical application in dermatology, oncology, rheumatology and immunology (for general monographies see Sporn, Roberts and Goodman (Eds.), The Retinoids, vol. 1 and 2, Academic Press, Orlando, 1984; Sporn and Roberts, CIBA FOUND. SYMP., 113, 1 (1985); Sporn, Roberts and Goodman (Eds.), The Retinoids: Biology, Chemistry and Medicine, 2nd ed., Raven Press, New York, 1994; Dawson and Okimura (Eds.), Chemistry and Biology of Synthetic Retinoids, CRC Press, Boca Raton, 1990; Packer (Ed.), Methods in Enzymology, Academic Press, vol. 189, part A, 1990 and vol. 190, part B, 1991)). The clinical application of synthetic retinoids in the management of recalcitrant and previously incurable neoplastic, inflammatory and keratinization disorders has introduced a real revolution in dermatology and other medical fields (Tsambaos, DERMATOSEN, 44, 182 (1996), Muindi, CANCER TREAT. RES., 87, 305 (1996)). By regulating gene expression, retinoids are capable of regulating the differentiation and growth of transformed cells or of inhibiting the malignant transformation of a variety of cells reversing their differentiation (DeLuca, FASEB J., 5, 2924 (1991), Lotan and Glifford, BIOMED. PARMACOTHER., 45, 145 (1991)). In the mechanisms of regulation of gene expression by retinoids certain members of the large family of steroid and thyroid gland hormones receptors are involved, that is nuclear proteins to which retinoids specifically bind (DeLuca, FASEB J., 5, 2924 (1991), Leid et al., TRENDS BIOCHEM. SCI., 17, 427 (1992)). Retinoid receptors have been already isolated and studied (Redfern, PATHOBIOL. 60, 254 (1992), Giguere et al., NATURE, 330, 624 (1987), Petkovich et al., NATURE, 330, 444 (1987)). They act as transcription factors following activation by suitable ligands. Currently, the development of new retinoid-based drugs is based on the synthesis of novel ligands for the retinoic acid receptors RARα,β,γ and RXRα,β,γ and the orphan receptors (Lippman and Lotan, J. NUTR. 130(2S Suppl), 479S (2000)).
It has been recently reported that natural retinoids, like retinoic acid and retinol, as well as synthetic analogues of retinoic acid, e.g. isotretinoin (13-cis-retinoic acid), acitretin and the arotinoids Ro 13-7410, Ro 15-0778, Ro 15-1570 and Ro 13-6298 but also other compounds, e.g. calcipotriol, anthralin and their combination, known for their antipsoriatic activity, inhibit the enzyme ribonuclease P (RNase P) (Papadimou et al., J. BIOL. CHEM. 273, 24375 (1998), Papadimou et al., SKIN PHARMACOL. APPL. SKIN PHYSIOL. 13, 345 (2000), Papadimou et al., EUR. J. BIOCHEM. 267, 1173 (2000), Drainas et al., SKIN PHARMACOL. APPL. SKIN PHYSIOL.13, 128 (2000), Papadimou et al., BIOCHEM. PHARMACOL. 60, 91 (2000)), which has been isolated and characterized from the slime mold Dictyostelium discoideum (Stathopoulos et al.; EUR.J. BIOCHEM. 228, 976 (1995)) and from normal human epidermal keratinocytes.(Drainas et al, unpublished results). These finding advocate the hypothesis that retinoids, in addition to regulating DNA transcription, can also regulate the activity of enzymes playing key-roles in macromolecular biosynthesis, by their implication in post-transcriptional processes, in which binding to the retinoic acid receptors is not involved. RNase P is responsible for the ripening of the 5′ terminus of precursor tRNA molecules. RNase P activity have been found in all pro- and eucaryotic organisms studied so far (Frank and Pace ANNU. REV. BIOCHEM. 67, 153 (1998)). RNase P enzymes are complexes of RNA with proteins and their activity is mainly attributed to their RNA subunit. Several findings indicate that the structure of the RNA subunit is of similar size in pro- and eucaryotic organisms and that the structures of RNase P from different eucaryotic organisms are similar. For these reasons, it appears that RNase P from D. discoideum and human epidermal keratinocytes are good models for the identification and development of new inhibitors.